Organ perfusion device

ABSTRACT

A device and methods for perfusing organs by controlling either the perfusion pressure or the perfusate flow rate. The operator may select either method of perfusion control. Also provided are devices and methods for perfusing multiple organs simultaneously on the same device.

BACKGROUND OF THE INVENTION

The present invention relates generally to organ perfusion devices andtechniques of organ perfusion. In particular, the perfusion devices maysimultaneously perfuse more than one organ in an independent manner. Theperfusion devices may also perfuse organs at either constant perfusionpressure or constant perfusate flow rate, at the discretion of theoperator. Methods are provided for simultaneously perfusing multipleorgans, perfusing organs on devices capable of regulating both the flowrate and pressure of a perfusate, and measuring the effect of astimulus, chemical or otherwise, on organ function.

Maintaining viability of animal organs following removal of the organfrom the animal's body (ex vivo viability) or during isolation of theorgan from the animal's natural circulation is of great importance formedicine, pharmacology, and physiology. Traditionally, excised solidorgans have been maintained through a combination of hypothermia andexposure to nutrient solutions. Hypothermia decreases the metabolicactivity of cells within the organ. The decreased metabolic activitylowers the cells' demand for nutrients and oxygen while concurrentlysuppressing the production of toxic waste products. Exposure to nutrientsolutions serves two functions. First, the cells of the isolated organmay be exposed to nutrients and/or oxygen. Second, toxic waste productsare removed as the solution is washed over or through the organ.

Devices previously used for maintaining ex vivo organ viability haverelied on three methods of nutrient solution exposure. In perfusion, theisolated organ is bathed in a nutrient containing culture medium. Whilethis method is effective for bone marrow or other non-solid organpreservation, perfusion does not optimize solid organ preservation asnutrient supply to the interior of the organ relies on diffusion throughthe more superficial organ tissue.

Perfusion is a method of administering the nutrient solution through thevascular bed of an organ. The nutrient solution is fed into the arterialside of the organ's vascular system. The solution follows the naturalcirculatory path of the organ and exits the venous side of the organ'scirculation. Superfusion combines both perifusion and perfusion of asingle organ.

The devices providing perfusion or superfusion of isolated organsregulate the perfusate flow rate or the perfusion pressure, but notboth. Organs perfused by devices regulating only the perfusion pressuretypically do not have a constant flow of perfusate to the organ. As theblood vessels in the organ dilate or constrict, either naturally or inresponse to an external stimulus such as hypothermia, the perfusionpressure changes. The perfusion device adjusts the flow rate of theperfusate so as to maintain a constant pressure. As blood vesselsconstrict, the perfusate flow rate decreases in order to maintain aconstant perfusion pressure. Decreasing perfusate flow can cause hypoxiaand injury to the isolated organ. As blood vessels dilate, the perfusateflow rate increases to maintain a constant pressure. Increased perfusateflow can cause electrolyte and free water imbalances resulting in edemaand functional alterations. Presently available perfusion devices do notprovide a means to control both the pressure or flow rate of perfusateinto the isolated organ at the discretion of the operator.

Ex vivo viability is of obvious importance for organ transplants.Because the tissue type of transplanted organs must be compatible withthe tissue type of the recipient, available organs must often betransported over long distances for long periods of time to reach acompatible recipient. Also, the demand for transplant organs is greaterthan the supply, necessitating optimized use of limited resources. Organviability must be optimized during this waiting period to achieve themost effective results. Devices presently employed for organ transplantand preservation neither monitor the physiological state of thetransported organ nor respond to organ changes by altering thepreservation conditions under which the organ is being maintained. Thus,preventable organ damage may occur during transport. As more diseasesare treated by transplantation, especially with fragile organs,optimizing preservation conditions will assume even greater importance.

Also, ex vivo therapies are being developed for the treatment of variousdiseases. For example, ex vivo lymphocyte stimulation and activation hasbeen employed for the treatment of AIDS-related diseases. Ex vivotherapy may also provide a means to expose an organ to high doses of atherapeutic modality while protecting other organs from the therapy.Cancer chemotherapy is one such example. Solid tumors, such ashepatomas, do not respond well to doses of chemotherapeutic agents thatare tolerable to the bone marrow. Ex vivo treatment of the liver couldprovide very high drug doses to the tumor while sparing the bone marrow.For effective ex vivo treatment, however, the organ must be perfused soas to optimize viability. Hence, the perfusion device must be capable ofdelivering adequate levels of perfusate to the organ, monitoring thefunction and viability of the treated organ, and responding to changesin organ function during treatment. Presently available perfusiondevices can not monitor and respond to physiological changes in theisolated organs.

Circulatory isolation of organs within the body is also desirable formedical treatment. If an organ can be perfused in isolation whileremaining in the body, many of the advantages of ex vivo therapy may berealized with less morbidity. Catheters that selectively occlude bloodvessels leading into and out of a solid organ may be used to selectivelyperfuse the organ with a therapeutic substance. As in ex vivo therapy,high levels of a drug could be delivered to the diseased organ withoutrisking potentially toxic side-effects in other organs. Also like exvivo therapy, the perfusion device should be capable of deliveringadequate levels of perfusate to the organ, monitoring the function andviability of the treated organ, and responding to changes in organfunction during treatment. Otherwise permanent damage to the treatedorgan could occur.

Isolation of organs from the host circulation, either by organ removalor in vivo circulatory isolation, is also valuable for assessing thepharmacological or toxicological effects of compounds on individualorgans. Because a single compound can affect many different organsystems it is often difficult to differentiate the direct effect of thecompound on the organ from the effect of the other host responses to thecompound. Isolation of the organ from the systemic response of the hostprovides a means to directly measure the effect of the compound on theorgan. Physiological responses to naturally occurring compounds can besimilarly assessed. Presently available perfusion devices do not providethe monitoring or perfusate regulating capabilities necessary forassessing complex organ functions or optimizing organ viability.

Measurement of an organ's response to physical stimuli, such ashypothermia, blunt trauma, electrical stimulation, and the like, is alsobest evaluated by isolating the organ. Similar to measurement ofchemical effects on an organ, isolation of the organ eliminates theconfounding effects of other host responses. For optimal monitoring,perfusion devices must be capable of altering perfusion characteristics,such as pressure, to differentiate organ effects from vascular effects.For example, hypothermia causes vasoconstriction resulting inhypoperfusion of the organ. Because the delivery of oxygen and othernutrients is altered by the vascular response, the changes in organfunction could result from either from cellular effects of the externalstimulus or the vascular response to the stimulus. Present perfusiondevices do not allow differentiation of these factors.

Devices exist which monitor and adjust the condition of cell culturemedia. See, e.g., U.S. Pat. Nos. 4,618,586 and 4,629,686. Organperfusion has special requirements not met by cell culture perfusiondevices, however. As noted above, constant pressure perfusion can oftenresult in differences in organ perfusion volume. This difference inperfusate volume can affect the organ's viability and function. A devicewhich provides constant flow perfusion would alleviate this problem.Unfortunately, constant flow perfusion is not always appropriate, suchas during extreme vasoconstriction or vasodilation. Comparison to otherresearch often requires constant pressure perfusion also. Hence, itwould be preferable for perfusion devices to operate under eitherconstant pressure or constant flow. Perfusion devices available in theart can only perfuse by constant pressure or constant flow.

Physiological or pharmacological research also requires that treated orstimulated organs be compared to control organs. Ideally, the controlorgan receives identical perfusate at the same temperature, pH, pO₂,pCO₂, etc. Unfortunately, slight variations in perfusate compositionsoften occur which can alter the normal organ function. Because thebaseline functions of the control organ and the test organ are alteredby the perfusate differences, it is difficult to accurately interprettest data. A means to deliver perfusate to both organs from the samesource would overcome this difficulty and allow for more accuratephysiological and pharmacological assessments. Presently availableperfusing devices do not fulfill this need.

Even though the test organs and control organs may not be studied underidentical conditions, it is necessary to gather both sets of data inmodern research. Conducting two sets of tests is time consuming andlaborious for laboratory personnel. A device which would study both thetest organ and control organ simultaneously would provide a means toincrease laboratory productivity and lower the cost of research. Inlight of the steadily rising cost of research and the increasingscarcity of funding, a means to generate both test data and control datasimultaneously is of great importance.

What is needed in the art are perfusion devices which monitor organfunction during perfusion, adjust the perfusion conditions to optimizeorgan viability, provide a means to simultaneously perfuse test organsand control organs with identical perfusate, and are appropriate for invivo, ex vivo, and in vitro use. Quite surprisingly, the presentinvention fulfills these and other related needs.

SUMMARY OF THE INVENTION

The present invention provides organ perfusion devices comprising afirst fluid conduit fluidly connecting a source of a perfusate to anupstream pump, a second fluid conduit for fluidly connecting theupstream pump to an organ, a means to regulate the pressure of theperfusate in the second fluid conduit, and a means to regulate the flowrate of the perfusate through the second fluid conduit. The means toregulate the pressure of the perfusate and the means to regulate theflow rate of the perfusate may be an upstream sensor and a pump speedcontrol mechanism.

Also provided are devices for the simultaneous perfusion of a pluralityof individual organs comprising, one or more upstream pumps equal innumber to the number of individual organs being simultaneously perfused,one or more first fluid conduits connecting each pump to a source of aperfusate, and one or more second fluid conduits connecting the arterialsystem of each individual organ with a single upstream pump, whereineach upstream pump is connected to only one organ.

Methods for perfusing at least one organ to maintain organ viability arealso provided. Generally, the methods comprise connecting the arterialsystem of each organ to separate pumps by means of at least one fluidconduit, which pumps are connected to a source of a perfusate, andadministering the perfusate to each organ by independently regulatingeach pump to adjust the pressure or flow rate of the perfusate in thefluid conduit.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a schematic diagram of a perfusion device forperfusing multiple organs constructed in accordance with the principlesof the present invention.

FIG. 2 illustrates a schematic diagram of a perfusion device capable ofaltering perfusion characteristics so as to optimize organ viability forperfusing a single organ constructed in accordance with the principlesof the present invention.

DETAILED DESCRIPTION OF THE SPECIFIC EMBODIMENTS

According to the present invention, devices and methods are provided forperfusing solid animal organs. Solid organs are those organs which havean identifiable vascular system for carrying blood with separate inflowand outflow vessels. Solid organs which may be perfused by the presentinvention include hearts, kidneys, livers, thyroids, lungs, intestines,pancreases, reproductive organs, brains, spleens and the like. Theorgans of any animal may be perfused, provided that the vascular inflowvessel is of sufficient size to accommodate a fluid conduit. The organsource will generally be mammalian, such as mouse, rat, dog, cat, orhuman, although other animal species may be appropriate for differentapplications.

One embodiment of the present invention provides an organ perfusiondevice having a source of a perfusate, a first fluid conduit fluidlyconnecting the source of a perfusate to an upstream pump, a second fluidconduit for fluidly connecting the upstream pump to an organ, a means toregulate the pressure of the perfusate in the second fluid conduit, anda means to regulate the flow rate the perfusate through the second fluidconduit.

As used herein, when component A is "upstream" or "proximal" tocomponent B, unrecycled fluid from the source of the perfusate flowsthrough component A before flowing through component B during the normaloperation of devices of the present invention. Likewise, component B is"distal" or "downstream" of component A when unrecycled fluid from thesource of the perfusate flows through component B after flowing throughcomponent A during the normal operation of the devices of the presentinvention.

The source of a perfusate is not critical and may vary. Typically thesource will include at least one reservoir capable of holding fluids.Generally about 4 reservoirs are employed, although this is not criticaland may vary. The reservoirs may be glass, stainless steel, plastic orthe like. The reservoirs may be closed and sterilized as appropriate.Likewise, the perfusates may be sterile, such as commercially availableRingers Lactate, normal saline, plasma, high oxygen transferencesolutions, anticoagulated whole blood or components thereof, or thelike. For selected applications, such as ex vivo high dose radiationtherapy, the patient may be the perfusate source. In this instance,whole blood, anticoagulated with sodium citrate, heparin or the like mayserve as the perfusate. Other perfusate solutions are well known in theart.

Multiple reservoirs may be employed, each containing a different fluid.The fluids may be mixed in a predetermined ratio producing a perfusatemixture of a desired composition. During perfusion, the composition ofthe perfusate may be varied by altering the ratio of the differentcomponent fluids in the mixture. For example, one fluid may containsodium bicarbonate (NaHCO₂). The pH of the perfusate mixture can bealtered by varying the amount of NaHCO₂ fluid in the mixture. If anorgan becomes acidotic during perfusion, the perfusate mixture can beadjusted, to increase the NaHCO₂ concentration thereby correcting theacidosis.

When multiple reservoirs are employed, a mixing means to selectively mixthe fluids from the different reservoirs is employed. By "selectivelymix" it is meant that the fluids are mixed in selected volumetricratios. The volumetric ratios may be predetermined and constant or maybe altered during perfusion. Typically, the volumetric ratios arealtered in response to changes in organ function in order to optimizeorgan viability. A fluid conduit connects the reservoirs to the mixingmeans. By "fluid conduit" it is meant any means of directing the fluidfrom one component of the device to another component of the devicewhich, except for the proximal and distal openings which connect to thedevice components, is closed. While generally the fluid conduit meanswill be tubing, such as polyethylene, silicone, or Tygon® tubing,alternative means are also envisioned, e.g., bored channels throughsolid supporting structures.

Conveniently the mixing means may be an electronic valve, such as theCavro Electric Motor Valve, Cavro Corporation. Other mixing means areacceptable, e.g., the device described in U.S. Pat. No. 4,629,686,incorporated herein by reference. Persons of skill in the art willreadily appreciate that different valves are appropriate for differentuses depending on the size of the organ being perfused, viscosity of theperfusate, cellular content of the perfusate, etc. The electronic valveindependently controls the flow rate of each different fluid into acommon flow line such as polyethylene, silicone, or Tygon®tubing, or thelike. The electronic valve may be controlled directly by the operator orthrough electronic means, such as a computer which alters thecomposition of the perfusate mixture in response to externally createdsignals. Alternatively, the mixing means may be a manual valve device.

After mixing has occurred, or directly from a single reservoir asappropriate, the perfusate may flow through filters, an oxygenator,and/or a heat exchanger, all connected by fluid conduits. The filtersmay also include a one way valve to avoid backflow into the reservoirs.Suitable filters include, e.g., The Whatman 6702-3600 or Gilman 12158.

The oxygenator may be a membrane oxygenator, such as Sci. Med Ultrox I,and the like, or a hollow fiber oxygenator, such as CD Medical Oxy 10and Oxy 1 or Unisyn Fibertec Cell-Farm Hollow Fibers Oxygenator and thelike. The gas introduced by the oxygenator will generally be O₂, CO₂, ora mixture thereof. The pH of the perfusate may be adjusted by alteringthe CO₂ content of the perfusate. As the CO₂ content increases carbonicacid is formed, lowering the pH of the perfusate. Organ ischemia may betreated by increasing the O₂ content of the perfusate.

Typically, the oxygenator is placed in close proximity to the perfusedorgans. As the perfusate flows through conduits toward the organ, thetemperature and other characteristics may change. As the perfusatewarms, gasses introduced by the oxygenator may leave solution and formbubbles. The bubbles can then embolize in the organ causing infarction.Situating the oxygenator proximally near the perfused organs limits therisk of bubble embolization. A bubble trap may be placed between theoxygenator and the perfused organ if required, especially in therapeuticapplications.

The heat exchanger may serve to cool or warm the perfusate. Cooling isgenerally preferred for organ preservation, as described in "BasicConcepts in Organ Procurement, Perfusion and Preservation forTransplantation", Ed. Luis H. Toledo-Pereya, Acad. Press 1982,incorporated herein by reference. Ex vivo therapy may employ warmedsolutions in order to warm the organ to supraphysiological temperatures,as desired. The heat exchanger also provides a means to determine theeffect of environmental temperature changes on organ function. Asexplained above, the heat exchanger is typically placed proximally nearthe perfused organs to avoid heat transfer prior to entering the organ.

Upon exiting the source, the perfusate is channeled into a pump througha first fluid conduit. The pump is preferably a roller type pump, suchas those employing Master Flex Pump 7018-20, so as to minimize celllysis when cellular perfusates are employed. A heater circulating pumpmay be used in lieu of separate heat exchangers and pumps in someembodiments. Generally, the pump will be electrical, although for invivo perfusion a pneumatic type pump may be preferred to reduce the riskof electrical injury to the organ or patient. The pump propels theperfusate into a second fluid conduit.

The output of the pump is determined by pump speed. The pump speed isregulated in two modes, perfusion pressure or perfusate flow rate in thesecond fluid conduit. During perfusion, the perfusion pressure or theperfusion flow rate may be varied or held constant. The mode may also bechanged, either during perfusion or otherwise. Hence, the pump speed maybe changed in response to functional characteristics of the organ orregulated to a constant flow or a constant pressure. When controlled bya computer, the pump speed may be controlled so as to provide eitherconstant perfusion pressure or constant flow rate, provided theuncontrolled mode remains within a defined range. If the uncontrolledmode leaves the predetermined range, the controlled mode will beadjusted. For example, if the organ is being perfused at a constantperfusion pressure, the flow rate may be programmed so as to notdecrease below a certain level. If the organ vasoconstricts and the flowrate decreases below the allowed level, the perfusion pressure will beincreased to maintain the minimum allowable flow rate.

The pump speed is controlled by a pump speed control mechanism. The pumpspeed control mechanism will generally be responsive to inputs from acomputer or other electronic source. Inputs from the electronic sourcecontrols the pump speed control mechanism which in turn controls thespeed of the pump. In this way, the pump output is controlled by inputsto the pump speed mechanism. Alternatively, the pump speed controlmechanism may be responsive to manual inputs.

After exiting the pump, the perfusate is channeled into a second fluidconduit to the organ. The second fluid conduit terminates in thearterial system of the organ. Generally, the second fluid conduitcommunicates directly with the main artery of the organ, e.g., the renalartery in human kidneys, the testicular artery in human testes, etc. Inorgans having a plurality of arterial inputs or accessory circulation,e.g., the human heart, human lung, etc., each arterial input may beperfused from the pump by way of branching the second fluid conduit orby perfusing one artery while appropriately occluding all other enteringarteries.

The second fluid conduit may include an upstream sensor. Typically, theupstream sensor may monitor several characteristics of the perfusate inthe second conduit prior to entry into the organ. Perfusatecharacteristics which may be measured include temperature, pH,electrolyte concentration, pressure, flow rate, pO₂, pCO₂, and the like.Any electrolyte may be measured such as Na, K, Ca, C1, NaHCO₂, Mg, PO₄,or the like. Typically surface field effect sensors, such as MicroElectrode Sensors will be employed, although other sensors areacceptable.

The upstream sensors may be microsensors capable of insertion into thefluid conduits or organ's arteries. Multiple microsensors may also beemployed, e.g., a temperature probe disposed in close proximity to a pHprobe, disposed in close proximity to a flow probe, etc. In this wayseveral characteristics may be measured in a short length of fluidconduit by multiple sensors. Typically, the upstream sensors are placedjust upstream of the organ so as to best measure the perfusatecharacteristics within the perfused organ. Microsensors may be placedwithin the main artery of the perfused organ in some applications.

The upstream sensor generates signals representative of the measuredcharacteristics. The signals may be analog or digital. The signals aretransmitted to a decoding device which can display the characteristicsin real time, store the signals for future analysis, or both. Typicallythe signals are transmitted to a computer. When the upstream sensortransmits analog signals, an analog/digital converter may be interspacedbetween the sensor and the computer to convert the analog signals todigital signals. The computer may also generate inputs in response thesignals. The inputs may then be transmitted to the pump speed controlmechanism to alter or regulate the pump speed and hence control the modeof perfusion. Other inputs generated by the computer can be transmittedto the oxygenator to control the gas content of the perfusate, to theheat exchanger to control the temperature of the perfusate, and theelectronic valve to control the chemical composition of the perfusate.Software is commercially available which provides these functions, suchas Lab Windows®, produced by National Instruments of Austin, Texas,which can also be customized by the producer to meet individual needs.

After the perfusate leaves the second fluid conduit, it travels throughthe circulatory system of the organ. The organ may be contained in anorgan chamber. The organ chamber may be environmentally controlled ifappropriate. The organ may also be immersed in the perfusate or anothersolution the organ chamber. Immersion in a solution provides a means tomore precisely control organ temperature and fluid balance. The solutionmay be static or flow over the organ such as described in U.S. Pat. No.4,395,492, incorporated herein by reference.

As the perfusate flows through the organ's circulation, it is gatheredby the venous system and exits an organ vein, e.g., the human renalvein. The perfusate may openly drain from the organ or channeled into athird fluid conduit. The third fluid conduit may include a downstreamsensor similar to the upstream sensor. The perfusate characteristicsmeasured by the downstream sensor can indicate functional and metabolicattributes of the organ. For example, if a kidney is being perfused, theNa and C1 concentrations and the osmolality can provide an indication ofthe perfusion and viability of the kidney since the renal cortex willfilter electrolytes and alter the composition of the perfusate when thekidney is viable and fully perfused. When the kidney is ischemic,intra-renal circulatory shunts occur which alter the function of thekidney and hence the outflowing perfusate. Likewise, ischemia in aperfused heart can be detected by an increase in the lactateconcentration of the outflowing perfusate.

The downstream sensor will generate signals representing the measuredperfusate characteristics and transmit the signals to a decoding device.The decoding device will typically be a computer which can produceinputs in response to the signals. The inputs can be transmitted to thepump, oxygenator, or electronic valve as above. The downstream sensorgenerally is located just downstream of the organ. When microsensors areemployed, the downstream sensor may be placed within the primary vein ofthe perfused organ. Because organ function will generally be monitoredby a downstream sensor in the third fluid conduit, this provides themost accurate measure of the perfusate as it leaves the organ.

The third fluid conduit may empty the perfusate into disposal systemappropriate for the particular application. Alternatively, the thirdconduit may channel the perfusate back to the source of a perfusate forrecycling. In this case, the third conduit will generally include afilter, such as a as on Whatman 6702-3600, Gilman Filta 12158 or thelike, to remove contaminants or cells from the perfusate. The thirdconduit may also include a downstream pump to propel the fluid to thesource of the perfusate. The recycled perfusate will typically bereturned directly to the mixing means, although the fluid can bereturned to a reservoir.

Different components of devices of the present invention may bedisposable. For example, the fluid conduits may be standard tubingemployed for intravenous therapy. At least one fluid reservoir may be acommercially available container of intravenous fluid such as normalsaline. Other disposable components will be readily appreciated bypersons of skill in the art. Disposable components will be especiallyuseful for therapeutic applications.

Also provided are devices for the simultaneous perfusion of multipleorgans comprising one or more upstream pumps equal in number to thenumber of individual organs being simultaneously perfused, one or morefirst fluid conduits connecting each pump to a source of a perfusate,and one or more second fluid conduits connecting the arterial system ofeach individual organ with a single upstream pump, wherein each upstreampump is connected to only one organ. Generally, the organs are perfusedfrom a single source of perfusate. This provides a means to perfuse eachdifferent organ with identical perfusate or with perfusates differing inonly one characteristic or component. Generally the device will becapable of perfusing two organs, although this is not critical and mayvary. Each organ is supplied with perfusate propelled by separate pumps.The pump speed of each pump is controlled by separate pump speed controlmechanisms so that the pump speed of each pump may be controlledindependently from each of the other pumps. The pumps may independentlyoperate in either constant pressure mode or constant flow rate mode. Theperfusion pressure or the perfusion flow rate to each organ may beindependently regulated by this means.

In embodiments providing for the perfusion of multiple organs, thesecond fluid conduit is branched. The second fluid conduit has a singleproximal end connected to the source of a perfusate. Distal to thesecond fluid conduit's proximal end, the second fluid conduit branchesinto multiple passages so that each passage fluidly connects the branchpoint to each separate pump thereby connecting each pump to the sourceof the perfusate. Each multiple passage may include an oxygenator orheat exchanger so that the temperature, pH, pO₂, pCO₂, and the like maybe independently regulated to each pump and thus to each organ. In thismanner it is possible to vary one characteristic of the perfusate andstudy the effect of that variation on organ function.

Methods for perfusing organs employing devices which can regulate boththe perfusate flow rate or the perfusion pressure are also provided.Multiple organs may be simultaneously perfused on a single device by thedisclosed methods. The methods generally comprise connecting thearterial system of each organ to separate pumps by means of at least onefluid conduit, which pumps are connected to a source of a perfusate andadministering the perfusate to each organ by independently regulatingeach pump to adjust the pressure or flow rate of the perfusate in thefluid conduit.

A number of third fluid conduits are hermetically attached to thearterial system of each organ to be perfused. The conduits willgenerally be occlusive vascular catheters, although this is notcritical. The fluid conduits provide a means to deliver the perfusate tothe organ without fluid loss or contamination.

The perfusate flow through the second fluid conduit and into the eachorgan is regulated by a pump. The pump speed controls the flow rate ofthe perfusate. The flow rate is constant when the pump speed isconstant. The pump speed also contributes to the pressure of theperfusate in the second fluid conduit. At a constant vascular resistancewithin an organ, the pump speed is directly proportional to theperfusate pressure. Thus, by altering the pump speed the perfusatepressure can be altered. The pump speed may be regulated by an operatorto provide for constant perfusate flow rate or a constant perfusionpressure. Alternatively, the pump speed may be regulated by a computerthat receives signals from sensors that monitor characteristics of theperfusate. As the perfusate flow rate or perfusate pressure aremonitored, the pump speed can be adjusted by the computer to maintainconsistency or introduce desired alterations in perfusate flow rate orperfusate pressure.

Methods for perfusing organs so as to optimize the viability of theperfused organs are also provided. The organ to be perfused is connectedto a third fluid conduit and pump as above. The third fluid conduit hasa downstream sensor which measures different characteristics of theperfusate exiting the organ, such as pH, temperature, glucoseconcentration, pO₂, and the like. The downstream sensor generatessignals representing the measured characteristics. Typically the signalsare transmitted to a computer. The signals may be decoded and displayedfor the operator. The signals may also be analyzed by the computer andcompared to predetermined values. The computer can generate inputs inresponse to the comparison of the signals to the predetermined values.The inputs may be transmitted to a mixing means, an oxygenator, a heatexchanger or the pump connected to the organ to alter thecharacteristics of the perfusate entering the organ. In this manner,organ viability can be optimized by prompt detection and correction ofmetabolic or functional abnormalities of the organ.

Methods for determining the effect of a test substance on an organ arealso provided. At least two organs are perfused on a perfusion device ofthe present invention. One organ is exposed to the test substance byintroducing the test substance into the perfusate distal to the pump.Because each organ is perfused by a separate pump, the test substancemay be administered to only one organ when introduced to the perfusatedownstream of the branch point in the second fluid conduit. If the testsubstance is introduced upstream to the upstream sensor, theconcentration of the substance entering the test may also be determined.The effect on the test organ may be determined by comparing thecharacteristics of the perfusate leaving the test organ to those of theperfusate leaving the control organ as measured by downstream sensors.Alternatively, the effect of the substance on the test organ can bemeasured by means other than the characteristics of the perfusateleaving the organ, such as an intraventricular balloon to measurecardiac wall tension or contractility.

Referring now to FIG. 1, there is shown a schematic illustration of oneembodiment of a perfusing device constructed in accordance with theprinciples of the present invention. Like reference characters will beused to indicate like elements.

The illustrated embodiment is a device for simultaneously perfusing twoorgans. Multiple reservoirs 1 are able to hold different solutions. Thesolutions flow through individual tubing 2 from the reservoirs 1 to anelectronic valve 3. The electronic valve 3 regulates the flow of eachdifferent solution into a common tube 4 thereby producing the perfusate.The composition of the perfusate may be altered by changing the ratio ofthe flow rates of the different solutions through the electronic valve3. As the perfusate flows through the common tube 4 it is filtered by afilter 5. Following filtration, the perfusate continues through thecommon tube 4 and through an oxygenator 6. The oxygenator regulates thepO₂ and pCO₂ in the perfusate by means of exposing the perfusate to amixture O₂ and CO₂ from a gas source 7. Upon leaving the oxygenator 6,the perfusate continues through the common tube 4 into a heat exchanger8. The heat exchanger 8 regulates the temperature of the perfusate.After exiting the heat exchanger 8 the perfusate enters a first fluidconduit 9. The first fluid conduit 9 is comprised of a common firstfluid conduit 10 and branched first fluid conduits 11. The perfusatewhich flows into each of the branched conduits 11 is identical. Theperfusate then flows into upstream pumps 12 which pumps perfusate awayfrom the reservoirs 1 and toward the organs 15 located in organ chambers25. The perfusate is pumped into second fluid conduits 13. The upstreampumps 12 can regulate the pressure of the perfusate in the second fluidconduits 13 or the flow rate of the perfusate through the second fluidconduits 13. Characteristics of the perfusate are measured by anupstream sensor 14 located in the second fluid conduit 13. The upstreamsensor 14 is located just upstream of the perfused organs 15 so that themeasured perfusate characteristics will closely approximate thecharacteristics of the perfusate entering the organs 15. After theperfusate has flowed through the organs 15 the perfusate flows into athird fluid conduit 16. The perfusate is pumped by a downstream pump 17away from the organs 15. The third fluid conduits 16 channel theperfusate back to the electronic valve 3 for re-use. Previouslycirculated perfusate flows through a filter 18 before reaching theelectronic valve 3.

A computer 19 receives signals generated by the upstream sensors 14. Theupstream sensors 14 produce signals representing each of the measuredcharacteristics. The computer 19 may store the signals for future use,display the signals to the operators on a terminal display 20, oranalyze the signals and produce inputs in response thereto. The inputsproduced by the computer 19 in response to the signals from the upstreamsensors 14 representing the pH, pO₂, or pCO₂ may be transmitted to thegas source 7 to alter the gas mixture contacting the perfusate. In thismanner, any of these characteristics may be regulated in the perfusatewhich is entering the organs 15.

The inputs produced by the computer 19 in response to signals from theupstream sensors 14 representing the temperature of the perfusate may betransmitted to the heat exchanger 8 to alter the temperature of the heatexchanger 8. The temperature of the perfusate entering the organs 15 maybe adjusted in this manner.

The inputs produced by the computer 19 in response to the perfusionpressure or flow rate of the perfusate in the second fluid conduits 13may be transmitted to upstream pump speed control mechanisms 21. Thepump speed control mechanisms 21 control the speed of the upstream pumps12. The speed of the upstream pumps 12 may be controlled independently.The computer may produce inputs which will cause the pump speed controlmechanisms 21 to vary the speed of the upstream pumps 12 to regulate theperfusion pressure or the perfusate flow rate in the second fluidconduits 13 by controlling the pump speed.

An injection port 24 is located in one of the second fluid conduits 13.The injection port 24 allows for selective administration of testcompound, such as a pharmaceutical, toxin, hormone, or other substance,into only one of the organs 15. The injection port is located upstreamto the sensor 14 in the second fluid conduit 13. The sensor 14 maydetermine concentrations of the test substance in the perfusate. Thesingle injection port 21 located downstream from the common first fluidconduit 10 provides a method of perfusing two organs 15 with a perfusateidentical in all respects except the added test substance. In thismanner, accurate determination of the effect of the test substance onthe organ 15 is possible.

Referring now to FIG. 2, a perfusion device for perfusing a single organconstructed in accordance with the principles of the present inventionis illustrated. The embodiment in FIG. 2 monitors characteristics of theperfusate as it flows from the organ. As the characteristics aremonitored, the temperature, gas content, chemical composition, of theperfusion pressure, or flow rate perfusate flowing into the organ can bealtered in response to the characteristics measured in the perfusateflowing out of the organ.

Multiple reservoirs 1 may contain different solutions. The solutionsflow through tubing 2 into an electronic valve 3. The electronic valve 3mixes the solutions in controlled ratios to produce a perfusate withspecific characteristics. The electrolyte concentration, glucoseconcentration, pH, etc. may be controlled by the electronic valve 3.

Following mixing of the perfusate in the electronic valve 3, theperfusate flows into a common tubing 4. The perfusate flows through afilter 5 and into an oxygenator 6. The oxygenator 6 contacts theperfusate with a mixture of O₂ and CO₂. The mixture ratio of O₂ and CO₂is controlled by a gas source 7. After passing through the oxygenator 6,the perfusate continues through the common tubing 4 and into a heatexchanger 8. The heat exchanger 8 regulates the temperature of theperfusate.

After following through the heat exchanger 8, the perfusate flowsthrough the first fluid conduit 11. The perfusate goes through anupstream pump 12 which propels the perfusate away from the heatexchanger 8. The perfusate is pumped into the second fluid conduit 13.An injection port 21 is located in the second fluid conduit 13 to enablethe operator to administer a pharmaceutical, hormone or the like to theorgan 15. The perfusate flows into a first sensor 14 which can monitor aplurality of characteristics of the perfusate. The perfusate then flowsinto the organ 15. After circulating through the organ 15, the perfusateflows into the third fluid conduit 16. A downstream sensor 23 monitorscharacteristics of the perfusate as the perfusate leaves the organ 15.The perfusate is pumped by a downstream pump 17 through a filter 18 andback into the electronic valve 3. The electronic valve 3 can mix thereturning perfusate with solutions from the reservoirs 1 to recycle theperfusate.

The upstream sensor 14 and the downstream sensor 23 produce signalsrepresentative of the perfusate characteristics which are monitored. Thesignals are transmitted to a computer 19. The computer 19 may displaythe information represented by the signals in real time, store theinformation represented by the signals, or produce inputs in response tothe signals. The inputs may control the gas source 7, heat exchanger 8,pump speed control mechanism 21 and/or electronic valve 3. Because theinputs are produced and varied by the computer 19 in response to thesignals produced by the upstream sensor 14 and the downstream sensor 23,the computer 19 may adjust the composition and other physicalcharacteristics of the perfusate to optimize organ viability.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those of skill in the art that the components ofthe perfusion devices, the methods of organ perfusion, and othercharacteristics of the invention described herein may be modified orsubstituted in various ways without departing from the spirit and scopeof the invention.

What is claimed is:
 1. An organ perfusion device comprising:a firstfluid conduit fluidly connecting a source of a perfusate to a firstpump; a second fluid conduit for fluidly connecting the first pump to anorgan; a means to regulate the pressure of the perfusate in the secondfluid conduit; and a means to regulate the flow rate of the perfusatethrough the second fluid conduit, which pump has a pump speed that mayprovide either constant perfusion pressure, or constant flow rate thatallows the organ perfusion pressure to vary.
 2. The organ perfusiondevice of claim 1, wherein the means to regulate the pressure of theperfusate comprises an first sensor for measuring the pressure of theperfusate in the second fluid conduit and thereby producing a pressuresignal, and a pump speed control mechanism responsive to an input. 3.The organ perfusion device of claim 2, wherein the first sensor furthermeasures the flow rate of the perfusate in the second fluid conduit andthereby produces a flow rate signal.
 4. The organ perfusion device ofclaim 3, wherein the pressure signal and the flow rate signal aremonitored by a computer, which computer produces the input to the pumpspeed control mechanism.
 5. The organ perfusion device of claim 1,wherein the means to regulate the flow rate of the perfusate in thesecond fluid conduit comprises manual control of the speed of the firstpump.
 6. A device for the simultaneous perfusion of a plurality ofindividual organs comprising:one or more first pumps equal in number tothe number of individual organs being simultaneously perfused; one ormore first fluid conduits connecting each pump to a source of aperfusate; and one or more second fluid conduits connecting the arterialsystem of each individual organ with a single first pump, wherein eachfirst pump is connected to only one organ, wherein each first pumpoperates at a pump speed variable to regulate the pressure or the flowrate of the perfusate in the second fluid conduit.
 7. The device ofclaim 6, wherein the pump speed of each first pump is independent ofanother first pump.
 8. The device of claim 6, wherein each second fluidconduit further comprises an first sensor which monitors thetemperature, pH, pO₂, pCO₂, electrolyte concentration, flow rate, orperfusion pressure characteristics of the perfusate.
 9. The device ofclaim 8, wherein the first sensor monitors two or more of saidcharacteristics.
 10. The device of claim 6, wherein the source ofperfusate further comprises multiple fluid reservoirs, and a means toselectively mix the fluids from the different reservoirs.
 11. The deviceof claim 10, wherein the means to selectively mix the fluids comprisesan electronic valve.
 12. The device of claim 11, wherein the electronicvalve is controlled by a computer.
 13. The device of claim 10, furthercomprising a heat exchanger and an oxygenator.
 14. The device of claim6, wherein the organs are contained within at least one organ chamber.15. The device of claim 6, further comprising a plurality of third fluidconduits, which third fluid conduits fluidly connect the venous systemof each organ to the source of a perfusate.
 16. The device of claim 15,wherein each third fluid conduit has a second pump.
 17. The device ofclaim 15, wherein each third fluid conduit further comprises a secondsensor which monitors the temperature, pH, pO₂, pCO₂, or electrolyteconcentration characteristics of the perfusate.
 18. The device of claim17, wherein the second sensor monitors two or more of saidcharacteristics.